tbuckley/cabot-search huggingface dataset:
BIOM-32. DNA METHYLATION SUBCLASSES PREDICT THE BENEFIT FROM GROSS TOTAL TUMOR RESECTION IN IDH-WILDTYPE GLIOBLASTOMA PATIENTS
Authors: Richard Drexler, Ulrich Schüller, Alicia Eckhardt, Katharina Filipski, Tabea Hartung, Patrick Harter, Iris Divé, Marie-therese Forster, Marcus Czabanka, Claudius Jelgersma, Julia Onken, Peter Vajkoczy, David Capper, Christin Siewert, Thomas Sauvigny, Katrin Lamszus, Manfred Westphal, Lasse Dührsen, Franz Ricklefs
Journal: Neuro-Oncology (2022)

Abstract DNA methylation-based tumor classification allows an enhanced distinction into subgroups of glioblastoma. However, the clinical benefit of DNA methylation-based stratification of glioblastomas remains inconclusive. We performed a multicentric cohort study including 430 patients with newly diagnosed glioblastoma whose tumors were subjected to DNA methylation profiling. The primary outcome was overall survival (OS) and progression-free survival (PFS). Secondary outcomes were the prognostic relevance of EOR and MGMTpromoter methylation status as well as surgical benefit for recurrent glioblastoma. After stratifying patients in accordance with their DNA methylation subclasses RTK I, RTK II, and mesenchymal (MES), outcome analyses revealed no significant differences between these three methylation subclasses (p = 0.06). RTK I or RTK II tumors who underwent gross-total resection (GTR) or near GTR had a longer OS and PFS than partially resected patients (p &amp;lt; 0.01). In the MES subclass, no survival benefit for a maximized EOR was found (p = 0.33). In multivariate analysis, the therapy response-predictive value of MGMT promoter methylation was evident for RTK I (p &amp;lt; 0.01) and RTK II (p = 0.02) but failed to be an independent factor in the MES subclass (p= 0.06). For local recurrence, re-resection conveyed a progression-to-overall survival (POS) benefit (p &amp;lt; 0.01), which was evident in the RTK I (p = 0.03) and RTK II (p &amp;lt; 0.01) subclasses, but not in the MES subclass (p = 0.33).This study demonstrates a survival benefit from maximized EOR at surgery for newly diagnosed and recurrent glioblastomas of the RTK I and RTK II subclass but not the MES subclass. Hence, it needs to be carefully considered whether the MES subclass should be treated with maximal surgical resection, especially when located in eloquent areas and at time of recurrence.
SURG-18. VARIOUS APPLICATIONS OF INTRAOPERATIVE ELECTROCORTICOGRAPHY FOR EPILEPTOGENIC TISSUE MAPPING IN AWAKE GLIOMA SURGERY
Authors: Dongqing Sun, Eline Schaft, Bibi van Stempvoort, Maryse 't van Klooster, Tineke Gebbink, Jan Willem Dankbaar, Pieter van Eijsden, Maeike Zijlmans, Pierre Robe
Journal: Neuro-Oncology (2022)

Abstract New-onset epilepsy is a symptomatic expression of diffuse glioma and lowers the quality of life. Surgical resection could extend beyond the traditional lesionectomy and include the epileptic focus when permitted by neurological function. Intraoperative electrocorticography (ioECoG) is used during epilepsy surgery to estimate the epileptogenic tissue by mapping the irritative zone. We aimed to determine the added value of ioECoG for postoperative seizure control in patients with non-refractory, glioma-related seizures. We retrospectively included patients who underwent ioECoG-assisted (awake) tumor resection. The ioECoG tailoring strategy was based on electrographic seizures and interictal discharges (sporadic spikes, continuous spiking patterns, and sharp waves). The extent of resection (EOR) and the residual tumor volume (cm3) were quantified from pre- and postoperative magnetic resonance imaging. We used the Weibull regression model for multivariate time to event (seizure recurrence) analyses. Fifty patients underwent ioECoG-assisted surgery. IoECoG recorded eight (16%) spontaneous electrographic seizures. Seventeen patients had residual interictal discharges after tumor resection. Residual interictal discharges were significantly associated with shorter seizure-free period after surgery (HR = 3.1 [1.3 – 7.2], p-value = 0,01). This effect was especially prominent in primary high-grade glioma resections. Residual tumor volume and EOR did not associate with seizure outcome. We sampled 14 interictal spike-positive brain tissues (three inside and 11 outside the MRI abnormalities) for additional histopathological analyses. Tumor cells were found in all specimens. The overall sensitivity of interictal spikes for tumor infiltration was 78% (95%CI [56 – 93]) and the specificity was 100%. IoECoG could serve multiple purposes in brain tumor surgery. It can assist in intraoperative seizure detection. Complete resection of epileptic discharges may improve seizure outcome independently of rest tumor volume or EOR. IoECoG could help guide supramaximal resection to improve seizure control and assist patient counseling. Furthermore, interictal spikes might serve as markers for intraoperative tumor identification.
TMET-28. A METHOD FOR EX VIVO STABLE ISOTOPE TRACING IN SURGICALLY EXPLANTED GLIOMA ORGANOIDS
Authors: Mohamad El Shami, Milan Savani, Lauren Gattie, William Hicks, Timothy Richardson, Samuel McBrayer, Kalil Abdullah
Journal: Neuro-Oncology (2022)

Abstract Stable isotope tracing is a powerful method for elucidating tumor metabolism. While in vivo stable isotope tracing is one of the most faithful approaches for studying metabolic activity under pathophysiologically relevant conditions, this method is technically challenging and costly to perform. We therefore sought to optimize an ex vivo stable isotope tracing approach under conditions that recapitulate the in vivo tumor microenvironment (TME), focusing on three key features: cellular heterogeneity, nutrient availability, and oxygenation. Surgically eXplanted Organoids (SXOs) are 3-dimensional glioma models that retain the diverse cell populations in human brain tumors. We tested whether glioma SXOs can be cultured in Human Plasma-Like Medium (HPLM) under brain-relevant oxygen levels (5%) for the purpose of stable isotope tracing. We cultured SXOs in conventional media, HPLM for 24 hours, or HPLM for 120 hours under 5% oxygen. We observed no significant differences in markers of tumor architecture, cellular proliferation rates, or stemness profiles. We then performed stable isotope tracing in SXOs cultured in HLPM at 5% oxygen. We acclimated SXOs to HPLM for 24 hours or 120 hours before replacing media with either HPLM (unlabeled) or HPLM with 15N2 glutamine (labeled). 15N isotopic labeling patterns in various metabolites were compared between the 24- and 120-hour conditions by linear regression. These patterns were strongly concordant over time (r2 = 0.9544), indicating that steady-state metabolic fluxes are stable in these cultures. We then analyzed intermediates that occupy key nodes in amino acid metabolism, redox homeostasis, and nucleotide synthesis pathways and found similarly strong concordance between labeling patterns at the individual metabolite level. Our findings outline an effective approach for conducting ex vivo stable isotope tracing in heterocellular glioma models under conditions that mimic the TME. This approach may complement and enhance analogous in vivo methods to provide new insights into glioma metabolism.
NCOG-28. LEEDS LOW GRADE GLIOMA SERVICE 2010-2022: A 12-YEAR EXPERIENCE
Authors: Neeraj Kalra, James Livermore, Suzanne Spink, Gillian Boyer, Lianne O'Malley, Michael Flatley, Melissa Maguire, Sam Fairclough, Elizabeth Wright, Caroline Armstrong, Elisa Stephenson, Seonaid Ewan, Sara Cooper, Danielle Guy, David Saunders, Mark Igra, Jeremy Macmullen-Price, Stuart Currie, Arshad Zaman, Catherine Derbyshire, Arundhati Chakrabarty, John Gooden, Paul Chumas, Ryan Mathew
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION We present our 12-year experience of the surgical management of lower-grade gliomas (LGGs) by a multidisciplinary team in a large tertiary UK brain tumour centre. METHODS Retrospective analysis of all adult patients who underwent surgery in the Leeds Low Grade Glioma Service between January 2010 and January 2022. Data collected included demographics, procedure type, extent of resection, histological diagnosis, morbidity, mortality, tumour location, seizure control, adjuvant therapy, cognitive outcomes, progression-free survival (PFS) and overall survival (OS). Results were statistically analysed by Kaplan-Meier and Log Rank (Cox Proportional Regression Hazard) Testing (p&amp;lt; 0.05). RESULTS 254 patients underwent surgery between 2010-2022. Of these, 77 patients underwent a second resection surgery, 9 a third, and 1 patient had a total of 4 resections. 184 operations were carried out awake, 115 asleep and 42 patients underwent biopsy only. The most common histology at initial surgery was astrocytoma, IDH1m, WHO Grade 2 (41.7%) with oligodendroglioma, IDH1m, WHO Grade 2 being the second most common. The majority of tumors were located in the right frontal lobe (24%) followed by the left frontal lobe (18%). 32% of tumors were on the left side. The median time between diagnosis and first surgery was 36.5 months. 8 patients died during this time frame, 7 who had resection, 1 had biopsy. CONCLUSION Our experience of the surgical management of LGG over the last 12 years shows that maximal safe surgical resection remains important as first-line treatment. Greater extent of resection (EOR) can delay transformation, control seizures and improve survival. Awake surgery is well tolerated and can preserve eloquent function. A multidisciplinary team approach achieves the best outcomes, and is appreciated by our patients
NIMG-90. DIFFERENTIATION OF INTRACRANIAL SOLITARY FIBROUS TUMOR AND MENINGIOMA ON CONVENTIONAL, DIFFUSION-WEIGHTED, AND DYNAMIC SUSCEPTIBILITY CONTRAST PERFUSION MRI
Authors: Ryo Kurokawa, Mariko Kurokawa, Akira Baba, John Kim, Aristides Capizzano, Jayapalli Bapuraj, Ashok Srinivasan, Toshio Moritani
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND AND PURPOSE To evaluate the differences in the imaging findings of intracranial solitary fibrous tumor (SFT) and meningioma on dynamic susceptibility contrast (DSC) perfusion MRI, apparent diffusion coefficient (ADC), and conventional sequences. METHODS Between January 2016 and April 2022, the study enrolled 14 (median, 46 years [range, 25–74]; six females; seven with DSC-MRI) and 27 patients (median, 53 years [21–83]; 23 females; all with DSC-MRI) with pathologically proven SFT and meningioma, respectively. The normalized relative cerebral blood volume and flow (nrCBV and nrCBF), percentage signal recovery (PSR), normalized mean ADC (nADCmean), and conventional imaging features, including T1-weighted hyperintensity, were evaluated and statistically compared using Bonferonni correction. RESULTS PSR was significantly lower in SFT compared with that in meningioma (median, 22.5 [range, 6.4–48.8] vs. 70.1 [range, 18.6–104.2], p&amp;lt; 0.001). The majority of SFT showed mainly T1-weighted hyperintensities compared to the gray matter, while only one meningioma showed the finding (8/14 [57.1%] vs. 1/27 [3.7%], p&amp;lt; 0.001). No significant difference was observed in nrCBV, nrCBF, or nADCmean. CONCLUSIONS PFS was significantly lower in intracranial SFT compared with that in meningioma, indicating the difference in capillary permeability between the tumors. Comparing the hyperintensity on T1WI of the solid components with that of the cerebral cortex was a simple and useful characteristic to differentiate SFT from meningioma.
RADT-22. RISING UTILIZATION AND REDUCED MEDICARE SPENDING OF SHORT-COURSE RADIATION THERAPY FOR PRIMARY CNS TUMORS IN ELDERLY ADULTS
Authors: Kathryn Tringale, Alexandra Miller, Kathryn Beal, Jonathan Yang, Luke Pike, Brandon Imber
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION For elderly/frail glioma patients, shortening radiotherapy from 6 to 3 weeks (short-course RT [SC-RT]) is non-inferior to standard long course (LC-RT) though usage is estimated to be &amp;lt; 20%. We analyzed real-world utilization of SC-RT with/without systemic therapy in Medicare beneficiaries treated with RT for primary CNS tumors using CMS data on radiation episodes. METHODS Radiation modality, year, age (65-74, 75-84, ≥ 85), and site-of-care (freestanding vs hospital-affiliated) were evaluated. Utilization of SC-RT (11-20 fractions) vs LC-RT (21-30 fractions) and systemic therapy was evaluated by multivariable logistic regression. Medicare spending over the 90-day episode was analyzed using multivariable linear regression (adjusted β coefficients reported). RESULTS From 2015-2019, 9,572 episodes were included (2,966 [31%] SC-RT). SC-RT utilization increased (27% in 2015, 34% in 2019; OR 1.2 per year [95%CI:1.1-1.2]) and was associated with older age (age ≥ 85 vs 65-74, OR 7.0 [95%CI:5.7-8.7], hospital-affiliated sites (OR 1.2 [95%CI:1.1-1.4]), conventional RT (vs IMRT OR 2.8 [95%CI 2.4-3.3]), and lack of systemic therapy (OR 1.2 [95%CI:1.1-1.3]; p &amp;lt; 0.001 for all). Rise in SC-RT was concentrated in hospital-affiliated sites (interaction p = 0.005). Most (6,629, 69%) received systemic therapy with no differences by site-of-care (p = 0.34). Systemic therapy utilization increased over time (67% in 2015, 71% in 2019; OR 1.1 per year [95%CI:1.1-1.1]) and was less likely for older patients, conventional RT, and SC-RT (p-value &amp;lt; 0.001 for all). SC-RT significantly reduced spending vs LC-RT (β=$8,416, 95%CI:8,317-8,515), while spending modestly increased with systemic therapy usage (β=$316, 95%CI:220-409). CONCLUSIONS While most Medicare beneficiaries received LC-RT for primary brain tumors, SC-RT utilization increased in hospital-affiliated centers; despite high-level evidence, discrepancy in SC-RT implementation by site-of-care persists and necessitates further investigation. Given RT course length had a greater impact on Medicare spending than systemic therapy, increased use of SC-RT in appropriate populations reflects an opportunity to increase high value care.
NIMG-59. EVALUATION OF THE RESPONSE ASSESSMENT CRITERIA IN NEWLY DIAGNOSED AND RECURRENT GLIOBLASTOMA
Authors: Gilbert Youssef, Rifaquat Rahman, Camden Bay, Wei Wang, Mary Jane Lim-Fat, Omar Arnaout, Wenya Linda Bi, Daniel Cagney, Yuh-Shin Chang, Timothy Cloughesy, Matthew DeSalvo, Benjamin Ellingson, Elizabeth Gerstner, Luis Nicolas Gonzalez Castro, Jeffrey Guenette, Albert Kim, Eudocia Lee, J Ricardo McFaline-Figueroa, Christopher Potter, David A Reardon, Raymond Huang, Patrick Y Wen
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND We sought to compare the Response Assessment in Neuro-Oncology (RANO), modified RANO (mRANO), and immunotherapy RANO (iRANO) in a large population of patients with newly diagnosed (nGBM) and recurrent (rGBM) glioblastoma. METHODS Bidimensional measurements of enhancing disease and FLAIR sequence evaluation were performed by two independent readers on brain MRIs of consecutive patients with IDH-wildtype nGBM and rGBM treated at a single institution. Discrepancies were evaluated by a third reader. Dates of disease progression (PD) were identified using RANO, mRANO, iRANO, and other response assessment criteria variations. Spearman’s correlations between PFS and OS were calculated using iterative multiple imputations for censored observations. RESULTS 526 nGBM and 580 rGBM cases were included. Spearman’s correlations were not significantly different between RANO and mRANO in nGBM (0.69 [95% CI 0.62 to 0.75] vs. 0.67 [0.60, 0.73]) and rGBM (0.48 [0.40, 0.55] vs. 0.50 [0.42, 0.57]). Evaluation of FLAIR did not improve the correlation in patients who received antiangiogenic therapy. Acquisition of confirmation scans was associated with increased correlation only when PD was identified within 12 weeks of completion of radiation in nGBM. The use of the post-radiation MRI as a baseline was associated with increased correlation compared to use of the pre-radiation MRI in nGBM (0.67 [0.60, 0.73] vs. 0.53 [0.42, 0.62]). The correlation with iRANO was similar to RANO and mRANO among 98 patients with nGBM and 175 patients with rGBM who received immunotherapy. CONCLUSIONS RANO and mRANO demonstrated similar correlations between PFS and OS. The evaluation of FLAIR can be omitted, while confirmation scans were only beneficial in nGBM in the first 12 weeks after completion of radiation. There was a trend in favor of the post-radiation MRI as the baseline scan in nGBM. The use of iRANO criteria did not add a significant benefit in patients who received immunotherapy.
SURG-11. AKT1 E17K AND NF2 MUTATIONS DOMINATE SPINAL MENINGIOMAS WHO GRADE 1 AND PRESENT DISTINCT TUMOR FEATURES
Authors: Lingyang Hua, Majd Alkhatib, Matthias Meinhardt, Daniel Cahill, Priscilla Brastianos, Victoria Clark, Ganesh Shankar, Hiroaki Wakimoto, Gabriele Schackert, Tareq Juratli
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION While the mutational landscape of intracranial meningiomas has been extensively studied, our understanding of the molecular profile of spinal meningiomas (SM) remains incomplete. In this study, we correlate the molecular status with tumor features in a clinically well-characterized cohort. METHODS Samples from 50 patients (38 females and 12 males) with WHO grade 1 SM were collected. We performed next-generation sequencing (NGS) using an assay covering frequently mutated genes in meningiomas including AKT1, KLF4, NF2, PIK3CA, POLR2A, SMARCB1, SMARCE1, SMO, SUFU, and TRAF7. We correlated clinical and imaging data with the molecular tumor status. RESULTS AKT1 E17K mutations were detected in 15 (30%) and NF2 mutations in 32 (64%) patients. Both mutations were mutually exclusive. In contrast to AKT1-mutant intracranial meningiomas, AKT1-mutant SM only harbored a TRAF7 co-mutation in a single case. NF2-mutant meningiomas had a significant female predominance (n= 30/32, 94%) when compared to the balanced incidence of AKT1-mutant tumors (n= 7/15, 46.7%, p= 0.0006). The two groups demonstrated stark differences in the location: a thoracic localization was significantly more common in NF2-mutant meningiomas (n= 25/32, 78.1%, p= 0.0012), while meningiomas harboring an AKT1 mutation were predominantly located in the cervical spine (n= 11/15, 73.3%). Moreover, while a substantial proportion of NF2-mutant meningiomas developed in the dorsal location (n= 19/32, 59.3%), the vast majority of AKT1-mutant meningiomas (n= 13/15, 87%) arose ventral to the spinal cord. The histologic subtype of NF2-mutant meningiomas was variable, while all but one AKT1-mutant meningioma showed meningothelial histology (93.3%, p= 0.0001). All calcified meningiomas (n= 17) were NF2-mutant (p= 0.0002), whereas none of the AKT1-mutant meningiomas showed intratumoral calcifications. CONCLUSIONS Our findings support the central role of AKT1 and NF2 mutations in the molecular pathogenesis of WHO grade 1 SM. These mutations are mutually exclusive and are associated with distinct tumor and clinical features.
STEM-28. THE ROLE OF LONP1 IN DRIVING ENHANCED PMT IN THE 'LEADING EDGE' NICHE IN GLIOBLASTOMA
Authors: Javier Lepe, Chris Douglas, Kaijun Di, Nitesh Nandwana, Bhaskar Das, Daniela Bota
Journal: Neuro-Oncology (2022)

Abstract Glioblastoma (GBM), a high grade brain tumor, possesses poor overall survival with less than 5% surviving past five years. Previously, the TCGA classifications for GBM have included the mesenchymal, proneural, classical and neural subtypes with their own respective expression profiles and survival. Recent omics analysis has revealed other key aspects of GBM pathology, including intratumoral heterogeneity spanning all subtypes and enhanced stemness and treatment resistance and other hallmarks of proneural mesenchymal transition (PMT) following treatment with first-line standard of care treatment with radiation therapy and temozolomide (TMZ). Invading glioma stem cells (GSC) with high Nestin and hypoxia-inducible factor 1 alpha (HIF-1α) expression have been theorized to contribute to recurrence. HIF-1α acts as a master regulator driving increased stemness, invasiveness and angiogenesis. Interestingly, HIF-1α and nuclear respiratory factor-2 both upregulate Lon peptidase 1 (LonP1) in response to increased hypoxia or reactive oxygen species (ROS) production. LonP1 has been shown to drive increased metastasis, tumor growth and epithelial-mesenchymal transition (EMT), an analog of PMT, in colon cancer, melanoma and other cancer types. In a recently elucidated GBM organoid model, we present new findings demonstrating the importance of LonP1 in driving enhanced, transient PMT near the ‘invading edge’. This includes the enhanced expression of several key drivers of PMT and phenotypic hallmarks, such as increased invasiveness, proliferation and poorer survival.
IMMU-40. KINETICS OF DEXAMETHASONE-INDUCED ALTERATIONS OF DIVERSE IMMUNE SUBSETS IN VIVO
Authors: Nasser Yaghi, Masashi Watanabe, Matthew Watowich, Aiguo Li, Nicole Briceno, Omar Yaghi, Ferenc Livak, Shafiuddin Siddiqui, Karen Wolcott, Wei Zhang, Meili Zhang, Hua Song, Dionne Davis, Mark Gilbert
Journal: Neuro-Oncology (2022)

Abstract INTRODUCTION Immune therapeutic strategies are ideal for exploiting glial tumor heterogeneity. A limitation to their implementation for intra-axial brain tumors has been corticosteroids. Steroid use is associated with worse progression-free and overall survival when combined with some immunotherapies. Dexamethasone remains first line treatment for vasogenic cerebral edema and a primary therapy for immune-related adverse events secondary to immunotherapies. While used for decades, steroid immunosuppressive effects remain insufficiently characterized. We examined the temporal effects of dexamethasone on an extensive repertoire of immune cell subtypes. METHODS Non-tumor bearing C57BL/6 mice were treated with a onetime dose of 1 mg/kg dexamethasone via gavage, and peripheral blood was sampled at timepoints spanning 1 hour to 7 days. Flow cytometry was performed in triplicate to determine absolute cell counts of circulating B cells, CD8+ T cells (naive/memory), CD4+ T cells (naive/memory/regulatory), NK cells, neutrophils, monocytes, and eosinophils at each timepoint. We examined T cell function at multiple timepoints using an anti-CD3/CD28 bead stimulation assay. RESULTS At 1-hour post-treatment, cell counts across lymphoid subtypes increased. Neutrophils dramatically increased, while the remaining myeloid subtypes began to decrease. NK cells, similarly, were decreased in number. At 4-hours post-treatment all immune subtypes had their lowest circulating counts. There were corresponding increases in CD8+ and CD4+ T cell expansion and proliferation indices at 4-hours. By 24-hours post-treatment, all immune subtypes had recovered to or surpassed pre-treatment counts, except monocytes. By 7 days, the Tregs increased to 186% of pre-treatment counts, the highest of all subtypes, while eosinophils, monocytes, and NK cells never fully recovered to their pre-treatment baselines. CONCLUSIONS Understanding dexamethasone influence on circulating immune cells will inform optimal treatment timing for immunotherapies in brain tumor patients. We are further characterizing transcriptomic changes within immune cell subtypes following dexamethasone administration via population-level RNA sequencing over time.